Novel 1,2-benzothiazine dioxides

ABSTRACT

THE COMPOUNDS HEREIN ARE 1,2,3,4-TETRAHYDRO-11HYDROXYPYRAZINO(1,2-B)-1,2-BENZOTHIAZIN-1(2H)-ONE 6,6-DIOXIDES, USEFUL FOR THEIR PHARMACOLOGICAL PROPERTIES AND AS PRECURSORS FOR USEFUL COMPOUNDS.

United States Patent 3,787,401 NOVEL 1,2-BENZOTHIAZ1NE DIOXIDES Chris Royce Rasmussen, Ambler, Pa., assignor to McNeil Laboratories, Inc. No Drawing. Filed Oct. 2, 1972, Ser. No. 294,120 Int. Cl. C07d 93/02 US. Cl. 260-243 R 6 Claims ABSTRACT OF THE DISCLOSURE The compounds herein are 1,2,3,4 tetrahydro 11- hydroxypyrazino[1,2-b] 1,2 benzothiazin 1(2g) one 6,6-dioxides, useful for their pharmacological properties and as precursors tor useful compounds.

DESCRIPTION OF THE INVENTION This invention relates to novel 1,2,3,4-tetrahydro 11- hydroxypyrazino[1,2-b] 1,2 benzothiazin 1(2g) one 6,6-dioxidesand, more particularly, to those having the following formula:

wherein R is a member selected from the group consisting of hydrogen, loweralkyl, and CH CH R wherein R is a member selected from the group consisting of phenyl, cyano, and carboxyl. As used herein, loweralkyl means a straight or branched chain saturated aliphatic hydrocarbon containing from 1 to about 5 carbon atoms such as, for example, methyl, ethyl, propyl, isopropyl, pentyl, and the like.

The compounds of Formula I, except where are prepared by reacting ethyl 4-hydroxy-2g-L2-benzothiazine-3-carboxylate 1,1-dioxide (II) with an appropriate aziridine of Formula III in which R is as previously defined. This reaction is conducted in a suitable organic solvent such as, for example, an ether, e.g., ethyl ether, dioxane, tetrahydrofuran, and the like; a lower alkanol, e.g. methanol, ethanol, isopropanol, and the like; dimethabout 100 C. may be employed, with reflux generally ylformamide; and the like. Temperatures from ambient to preferred. This reaction may be illustrated by the following:

on \-COOC2Hs N r N H The compound of Formula I where R=CH CH COOH is prepared by nitrile-to-acid hydrolysis of the compound 3,787,401 Patented Jan. 22, 1974 Fee of Formula I where R:CH CH CN. This reaction may be illustrated by the following:

I N-CHaCHaC N N The subject Compounds I, other than when R=CH CH CN,

glacial HOAc H01; A

have been found to possess useful pharmacological properties indicative of central nervous system depressant activity as demonstrated by the following symptoms: ataxia or a decrease in either motor activity or muscle tone. For example, a decrease in motor activity is observed when R=loweralkyl at an intraperitoneal (i.p.) dose of about 300 mg./kg. body Weight in the mouse, and decreased muscle tone is observed when R=CH CH C-OOH at an i.p. dose of from about 10 to about rug/kg. body weight in the rat. Further, ataxia is observed when R=H or CH CH C H at oral doses of about 100 and about 300 mg./kg. body weight, respectively, in the mouse.

The subject Compound I wherein R=CH CI-I CN is useful as a precursor in the synthesis of the compound of Formula I where R=CH CH COOH.

The following examples are intended to illustrate, but not to limit, the scope of the present invention.

EXAMPLE I 1,2,3,4-tetrahydro-1 1- hydroxypyrazino[ 1,2-b] 1,2-

benzothiazin-HZQ-one 6,6-dioxide A solution of 26.92 g. (0.10 mole) of ethyl 4-hydroxy- ZE-1,2-benzothiazine-3-carboxylate 1,2-dioxide and 8.6 g. (0.20 mole) of aziridine in ml. of absolute ethanol is heated under reflux for 1.5 hours. The reaction mixture is then allowed to stand at ambient temperatures for about 15 hours, after which time the resulting solid is collected and dried. Recrystallization of this solid from acetone (charcoal) yields, as the desired product, l,2,3,4-tetrahydro-l1-hydroxypyrazino[1,2 b]1,2 benzothiazin 1 (2g)-one 6, 6-dioxide, M.P. 262-264 C. (sl. dec.).

Analysis.Calcd. for C H N O S (percent): C, 49.64; H, 3.79; N, 10.52; S, 12.04. Found (P rcent): C, 49.97; H, 3.85; N, 12.57, 10.76, 10.67; S, 12.28.

EXAMPLE H 1,2,3,4-tetrahydro-2- (B-phenethyl) -1 l-hydroxypyrazino [1,2-b]-1,2-benzothiazin-1(2E)-one 6,6-dioxide A solution of 13.46 g. (0.050 mole) of ethyl 4-hydroxy- 2E-1,2-benzothiazine-3-carboxylate 1,1-dioxide and 11.04

3 g. (0.075 mole) of N-(fl-phenethyDaziridine in 60 ml. of absolute ethanol is heated under reflux for about hours, and the resulting solid is filtered from the hot solution. Work-up of the mother liquor affords an additional crop of product, which is combined with the first crop and recrystallized from acetone-95% ethanol to yield as pure product, 1,2,3,4-tetrahydro-2-(B-phenethyD-ll-hydroxypyrazino[1,2-b] 1,2 benzothiazin-1(2g)-one 6,6- dioxide, M.P. 163.5165.5 C.

Analysis.Calcd. for C H N O S (percent): C, 61.61; H, 4.90; N, 7.56; S, 8.66. Found (percent): C, 61.53; H, 4.86; N, 7.57; S, 8.65.

EXAMPLE III Z-ethyl-l,2,3,4-tetrahydro-l l-hydroxypyrazino[1,2-b]- 1,2-benzothiazin-1 (2g) -one 6, 6-dioxide A solution of 13.46 g. (0.05 mole) of ethyl 4-hydroxy- 2g-l,2-benzothiazine-3-carboxylate l,l-dioxide and 5.33 g. (0.075 mole) of N-ethylaziridine in 60 ml. of absolute ethanol is heated under reflux for 6 hours, after which time it is allowed to stand at ambient temperatures for about 15 hours. The resulting crystals [M.P. (155) 156- 158 C.] are collected and are recrystallized from acetone-95% ethanol to yield, as pure product, 2-ethyl-1,2,3, 4-tetrahydro-11-hydroxypyrazino-[1,2-b] 1,2 benzothiazin-1(21I )-one 6,6-dioxide, M.P. (155) 156-159" C.

Analysis.-Calcd. for C H N O S (percent): C, 53.05; H, 4.80; N, 9.52; S, 10.89. Found (percent): C, 52.95; H, 4.81; N, 9.36; S, 10.91.

EXAMPLE IV 2 (2-cyanoethyl)-1,2,3,4-tetrahydro-1 l-hydroxypyrazino 1,2-b] -1,2-benzothiazin-1 (ZED-one 6, 6-dioxide To a heated and vigorously stirred solution of 26.92 g. (0.10 mole) of ethyl 4-hydroxy-2 H -1,2-benzothiazine-3- carboxylate 1,1-dioxide in 30 ml. of dimethylformamide is added dropwise a solution of 13 g. (0.15 mole) of N- (2-cyanoethy1)aziridine in 40 ml. of dimethylformamide. The reaction mixture is stirred for 15 minutes longer after the addition is complete and is then poured onto hydrochloric acid-ice water. The crystals which form are filtered ofi, yielding as desired product, 2-(2 cyanoethyl)-1,2,3,4-tetrahydro ll hydroxypyrazino[1,2-b]- l,2-benzothiazin-l(2l[ )-one 6,6-dioxide, M.P. 190192 C.

Analysis.-Calcd. for C H N O S (percent): C, 52.66; H, 4.10; N, 13.16; S, 10.04. Found (percent): C, 52.63; H, 4.24; N, 13.11; S, 10.03.

4 EXAMPLE v 1,2,3,4-tetrahydro-1 l-hydroxy-l-oxopyrazino [1,2-b]- 1,Z-benzothiazine-Z-propionic acid 6,6-dioxide A solution of 20.0 g. (0.06 mole) of 2-(2-cyanoethyl) l,2,3,4-tetrahydro 11 hydroxypyrazinoELZ b]-1,2- benzothiazin-l(2E)-one 6,6-dioxide in 250 ml. of glacial acetic acid and 250 ml. of 20% hydrochloric acid is refluxed for 10.5 hours. After the solvent is removed in vacuo, crystals of crude product appear, M.P. 183.5- C. Recrystallization of this crude material from ethanol-water yields as pure product, 1,2,3,4-tetrahydroll-hydroxy 1 oxopyrazino[l,2-b]-1,2-benzothiazine- 2-propionic acid 6,6-dioxide, M.P. 183l84 C.

Analysis-Calm. for C H N O S (percent): C, 49.70; H, 4.17; N, 8.28. Found (percent): C, 49.83; H, 4.30; N, 8.46.

What is claimed is:

1 A 1,2,3,4-tetrahydro 11 hydroxypyrazino[1,2-b]- 1,2-benzothiazin-l (ZED-one 6,6-dioxide having the formula:

z-R 1 s wherein R is a member selected from the group consisting of hydrogen, loweralkyl, fl-phenethyl, 2-cyanoethyl, and Z-carboxyethyl.

2. l,2,3,4-tetrahydro ll hydroxypyrazino[l,2-h]-1,2- benzothiazin-l (2g) -0ne 6,6-dioxide.

3. 1,2,3,4-tetrahydro-2-( fl-phenethyl) 11 hydroxypyrazino 1,2-b] -l,2-benzothiazin-1 (2E) -one 6,6-dioxide.

4. 2-ethy1-1,2,3,4-tetrahydro 11 hydroxypyrazino- [1,2-b] -l ,Z-benzothiazin-l (215;) -one 6,6-dioxide.

5. 2-(Z-cyanoethyl)-1,2,3,4-tetrahydro 11 hydroxypyrazino[ 1,2-b] -l,2-benz0thiazin-l (2g) -one 6,6-dioxide.

6. 1,2,3,4-tetrahydro 11 hydroxy-1-oxopyrazino[1,2- b]-1,2-benzothiazine-2-propionic acid 6,6-dioxide.

References Cited UNITED STATES PATENTS 3,408,347 10/ 1968 Shavel et al. 260-243 JOHN M. FORD, Primary Examiner US. Cl. X.R. 424246 P04 050 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION patent 3,787, 10]; Dated January 22 Q197 Inventor(s) Chris Royce Rasmussen It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

' o In 1., lil'lQi-Z 8'51, dime th -about C; sho ld read dimethyl-formamide; and the like. Temperatures from ambient to about 100 C. may be employed, with reflux generally preferred.

In Column 2, line #6, "LE-dioxid vshouldread -e- 1,1-dioxide Signed and sealed this 11th day of June 1971;. I

SEAL) rttest:

EDWARD M.FLE1CHER,JR. I c. MARSHALL mum rttesting Officer Commissioner of Patents 

